Isomerism of physiologically active agents in the solid state and in solution were reviewed and cases where the solid traps one of the isomers out of solution were emphasized. Several interesting examples of rotational, ring-chain, and cis-trans isomerism were selected for further study by a combined experimental-theoretical approach. This approach involves the study and comparison of isomerism in the solid state and in solution using X-ray crystallography, IR and NMR spectroscopy and theoretical calculations. In particular, we plan to study the proportion of isomers of pyrethrins, Schiff's bases, antihistamines, trihexphenidyl, methadone, and thioacylhydrazone in the solid state and in solution. These physiologically active agents will be studied using the IR-X-ray method, nmr spectroscopy, and the CAMSEQ program for theoretical conformational analysis. In addition, we plan to determine the crystal structures of several anti-cancer agents isolated from plants under the auspices of Dr. J.M. Cassady's National Cancer Institute contract. The goals of this research are to determine the factors responsible for differences in the proportion of the isomers of these compounds in the solid state and in solution. We are particularly interested in the effects of solvent and crystal packing forces on the isomer proportions. We also plan to continue our studies on the relationship between isomerism and biological activity. Our long-range goal is to determine the factors responsible for drug-receptor and enzyme-substrate binding using a combined theoretical-experimental approach which may eventually include large molecule X-ray crystallographic studies. The studies outlined in this proposal are an absolute prerequisite for such investigations, in order to lay the groundwork for such studies.